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Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4)

Byung Hak Ha1, Sezin Yigit1, Nalini Natarajan1

  • 1The Department of Pharmacology, Yale University, 333 Cedar St., New Haven, CT, 06520, USA.

Communications Biology
|November 17, 2022
PubMed

Insights

This study reveals how p21-activated kinase 4 (PAK4) binds to integrin β5, uncovering the molecular basis for this interaction and its effect on kinase activity.

Area of Science:

  • Cellular signaling
  • Molecular interactions
  • Integrin biology

Background:

  • Integrin receptors link extracellular signals to intracellular pathways.
  • Kinase interactions with integrin tails are known but poorly understood at a molecular level.

Purpose of the Study:

  • To elucidate the molecular basis of the interaction between p21-activated kinase 4 (PAK4) and integrin β5.
  • To identify the specific binding site and functional consequences of this interaction.

Main Methods:

  • Determined three crystal structures of PAK4-integrin β5 complexes.
  • Utilized site-directed mutagenesis to confirm the binding site.
  • Assessed integrin β5 phosphorylation by PAK4 and the effect on kinase activity.

Main Results:

  • Identified a specific binding site in the membrane-proximal region of the integrin β5 tail.
  • The integrin β5 tail binds to the kinase substrate-binding groove, positioning Glu767 at the phosphoacceptor site.
  • Integrin β5 is poorly phosphorylated by PAK4, and this interaction weakly inhibits PAK4 activity.

Conclusions:

  • Established the molecular basis for β5 integrin-PAK4 interactions.
  • Suggests a need to revise current understanding of the cellular roles of integrin-kinase interactions.

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